A Study of Relationship Between Serum Uric Acid, and Fasting Plasma Glucose in Type 2 Diabetes Mellitus Patients

The current study was conducted to observe the relationship between serum uric acid, lipid pro ile and fasting plasma glucose in type 2 DM patients. It was a cross-sectional study. A total of 618 participants were included in the study (203-healthy, 206-prediabetic and 209-T2DM). One way analysis of variance was used to compare the mean between these three groups. A linear regression model was used to ind the relationship between SUA and FPG in T2DM. The mean values of serum uric acid in pre-diabetes and T2DM (4.929±1.33 and 4.69±1.41 mg/dl, respectively) were lower compared to healthy (5.40±1.08 mg/dl). SUA showed a signi icant positive correlation with serum triglycerides in T2DM (p<0.05). The linear regression model showed that SUAwas inversely associatedwith FPG in T2DMafter adjustment for age and gender. The biological interrelationship observed in the current study raises the possibility of potential pathogenic overlap between SUA and FPG. SUA might be involved in a metabolic imbalance which in turn leads to T2DM.


INTRODUCTION
Diabetes mellitus is a potential epidemic in India. The prevalence of Type 2 Diabetes mellitus (T2DM) may increase drastically from 171 million in the year 2000 to 366 million by the year 2030 (Wild et al., 2004;Whiting et al., 2011). The aetiology for the development of T2DM is multifactorial. It is a genetic disease. Various environmental factors such as obesity, migration from rural to an urban area, and lifestyle modi ications may also be the causative factors. Among the various risk factors, obesity plays a signi icant role [3]. Indians with lower body mass index (BMI) has a high propionate of diabetes (Rao, 2011;Mohan and Deepa, 2006). Hence they are at equal risk as those who are in western countries with obesity (Zargar et al., 2000). Moreover, Indians are genetically predisposed to coronary artery disease because of dyslipidemia (Misra and Khurana, 2011). To reduce the cardiovascular disease burden that diabetes creates, diabetes patients must be screened at an early stage itself.
Many previous studies have found the relationship between serum uric acid (SUA) and various risk factors that cause cardiovascular disease. But there is a lack of clear causal mechanism.
Uric acid (UA) is obtained as the inal product of purine metabolism. UA reacts to oxidative stress based on its localization. Intracellular Uric acid has anti-oxidant role while extracellular have prooxidant property (Kang and Ha, 2014). Being an anti-oxidant, uric acid protects the cardiovas-cular system. It prevents the peroxidation of proteins and lipids, scavenges free radicals, and chelates transitional metal ions (Glantzounis et al., 2005). Its intrinsic anti-oxidant activity has been con irmed by the administration of UA in healthy volunteers and athletes, which, in turn, reduced reactive oxygen species production (ROS) (Waring et al., 2001). UA also acts as a pro-oxidant. The Xanthine-oxidase, which is an isoform of Xanthineoxidoreductase enzyme, generates ROS, which in turn induce endothelial dysfunction. This has been observed in an animal study on a rat. In rats, oxonic acid, which is an inhibitor of the enzyme, uricase has been administered. This has induced hyperuricemia which in turn raised blood pressure. (Sanchez-Lozada et al., 2007).
Some studies have found a positive relationship between elevated SUA and diabetes (Dehghan et al., 2008;Chien et al., 2008), few reported no correlation (Taniguchi et al., 2001;Modi and Sahi, 2018), and some have reported inverse relationship (Bandaru and Shankar, 2011;Bonakdaran and Kharaqani, 2014). The current study was undertaken to know the actual trend of SUA in healthy, prediabetic, and T2DM and the relationship between SUA and Fasting plasma glucose (FPG) in T2DM.

Study design
It was a cross-sectional study. The study was done after getting approval from the Institutional Human Ethics Committee, Chettinad hospital and research institute, Kelambakkam.

Inclusion criteria and exclusion criteria
Those who underwent a volunteer health check-up at Chettinad hospital and research institute from 1 st August 2019 to 30 th August 2020 were included in the study. The study participants included both genders from the age of 35 to 65 years.
A standard questionnaire was used to obtain personal history. Smokers and chronic alcoholics were excluded from the study. Those who suffer from systemic disorders like hypertension, renal disease, cardiovascular disease, and pulmonary disease were excluded from the study.

Anthropometric measurement and blood collection
Height, weight, and blood pressure were measured using a standard protocol. The formula used for calculating Body mass index was weight in Kg divided by height in meter squared. After ensuring that participants were under 12hours fasting, a venous blood sample was drawn under aseptic precautions. Baseline variables like glycated haemoglobin, FPG, Blood urea nitrogen, creatinine, uric acid, total cholesterol, Triglycerides, and High-density cholesterol were measured using Siemens RXL automated chemistry multi dimension system. The Calculated parameters were LDL-C and VLDL-C. The Friedewald formula was used to calculate LDL-C. VLDL-C was calculated by dividing TGL by 5.

Statistical analysis
SPSS software was used for doing statistical analysis. One way analysis of variance (ANOVA) was used to ind the p-Value between the mean of the variables between healthy, pre-diabetes, and T2DM. The correlation between serum uric acid and TC, TGL, HDL-C, LDL-C, and VLDL-C was found using Pearson's correlation coef icient test. The relationship between SUA and FPG was found using a simple linear regression model. Table 1 shows the mean values of healthy, prediabetes, and T2DM patients. A Statistically signi icant p-Value was obtained for the biochemical parameters HbA1c, FPG, UC, Creatinine, TC, TGL, LDL-C and VLDL-C. Variables such as age, BMI, WC and SBP also showed statistically signi icant p values. Table 2 shows Pearson's correlation analysis between SUA and Lipid pro ile among T2DM. A Signi icant and positive relation existed between   SUA and TGL. Also, there was a negative but not signi icant relation between SUA and HDL-C.VLDL-C also shows a signi icant positive correlation with SUA. Table 3 shows that serum uric acid was statistically signi icant and negatively related to FPG. Figure 1 shows a scatter plot with regression data between SUA and FPG. The Dependent variable was FPG. The igure shows a signi icant negative correlation between SUA and FPG in T2DM patients.

DISCUSSION
Previous few studies have shown a positive relationship between SUA and FPG (Dehghan et al., 2008;Chien et al., 2008), and a recent study has shown no correlation between SUA and FPG (Modi and Sahi, 2018). The inconsistent indings seen in previous studies might be due to the small sample size, more of aged participants, selection of participants from a particular group rather than the general population, in luence other factors like food habits, lifestyle, genetic and environmental factors, etc.
In the current study, as shown in Figure 1, a simple linear regression model adjusted for age and sex showed a negative and signi icant association between SUA and FPG in T2DM. These indings were supported by the previous study (Bandaru and Shankar, 2011).
A possible mechanism for the negative correlation between SUA and FPG may be due to inhibition of uric acid reabsorption in the proximal convoluted tubule by the high level of glucose concentration in the kidney (Tuomilehto et al., 1988;Herman et al., 1976). The kidney mainly regulates glucose homeostasis. In normal circumstances, plasma glucose is freely iltered, and the majority of them are reabsorbed by sodium-dependent glucose transporter. Both Uric acid and glucose are reabsorbed at the same site in the proximal tubule. Hence, Glucose levels in luence the uric acid excretion by regulating the reabsorption of uric acid in the proximal tubule of the kidney.
Uric acid, which has intrinsic anti-oxidant activity, is reduced in pre-diabetes and T2DM. It may be one of the potential causes of oxidative stress in T2DM.

CONCLUSIONS
Our study has con irmed that there exists an inverse relationship between SUA and FPG in T2DM patients. Further studies with data on the levels of uric acid in the urine of T2DM patients would better reveal the underlying mechanisms for the associa-tion between SUA and FPG.